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Providing neuroprotection, interrupting cell death important to glaucoma research
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New drugs and parameters for clinical trials measuring neuroprotection have been developed, and researchers are finding that the area may finally reach clinical application in the future.
Drugs that treat intraocular pressure (IOP) may be able to interrupt optic nerve death, which researchers say is the final common pathway for all optic neuropathies. Evan B. Dreyer, MD, PhD, is a glaucoma specialist at the University of Pennsylvania Scheie Eye Institute. He has focused his clinical efforts on controlling glaucomatous blindness, and his research efforts are directed at understanding glutamate-mediated neuronal death.
In a roundtable discussion organized by Ocular Surgery News (“Neuro-ophthalmologists define neuroprotection,” June 1, 1999, pages 52-55), Dr. Dreyer said, “Clinically, we are trying to save the retinal ganglion cells, but the tools that we have are not quite as much on the cutting edge as one might hope. So I can do more to save the ganglion cells in a rat than I can do in a human, but we are in the process of changing that as quickly as we can from the bench investigation to where it becomes clinically useful.”
Pressure is important
Dr. Dreyer said that researchers know that pressure is important in managing at least one subset of glaucoma patients. He added, though, that it does not solve the problem in all patients and it is not the only answer to glaucoma. “It is the clinical obsession because it is what we know how to deal with,” he said. “We do not have neuroprotective drugs that we can prescribe. We do not have devices for retarding ganglion cell loss as of yet, with the exception of pressure-lowering agents.”
In the roundtable discussion, Dr. Dreyer defined neuroprotection. “What we have come to mean by neuroprotection is agents that protect the ganglion cells from dying without necessarily disturbing IOP,” he said. “One takes drops to lower the eye pressure not because we are worried about pressure per se, but because we want to save the optic nerve. That is neuroprotection at its most basic.”
Dr. Dreyer said neuroprotection has taken on a different meaning. Now, it refers to saving the optic nerve from glaucomatous optic neuropathy without necessarily lowering IOP.
Similarities in optic neuropathies
Leonard A. Levin, MD, PhD, is assistant professor of ophthalmology, visual sciences, neurology and neurological surgery at the University of Wisconsin in Madison.
Dr. Levin said in the Ocular Surgery News roundtable that the commonality of optic nerve disease and glaucoma is based on the fact that the initial damage is axonal. “And the beautiful thing about this is there is a large body of research that has been around for years that continues to study exactly what other mechanisms by which damage to the axon causes the cell body to die, because it is an indirect death as opposed to a direct death,” he said.
Because it is indirect, Dr. Levin explained, it often takes longer to occur than in a central retinal artery occlusion, for example. He said that this lends itself to a therapeutic potential for dealing with optic nerve disease, including glaucomatous optic neuropathy. “There is more of a window of opportunity to deal with these kinds of diseases than in diseases where the initial damage occurs in the cell body. And so this is one of the primary things that brings optic nerve disease together with glaucomatous optic neuropathy, and it is a very important difference.”
Clinical trials in early stages
Robert N. Weinreb, MD, told Ocular Surgery News (“Diagnostic tools could help with neuroprotection trials,” April 15, 2000, pages 70 and 71) that the challenge of neuroprotection is to demonstrate that a drug effectively protects the function or structure of the optic nerve. This will require longer-term studies with larger numbers of patients.
Clinical studies of neuroprotection are difficult and time consuming because glaucoma progresses slowly, and any clinical trial will require a much larger number of patients and will take longer than studies that measure only IOP. “It is possible that the length of these studies and the number of patients can be shortened by either recruiting patients who are at higher risk for disease or by using more sensitive diagnostic techniques for determining visual function and optic nerve structure,” Dr. Weinreb said.
“It is absolutely essential,” he added, “that visual function testing and evaluation of the optic disc and retinal nerve fiber layer be employed in clinical trials if one is going to discover whether a drug is neuroprotective or not.”
Dr. Levin said that masked, randomized clinical trials of neuroprotective agents have shown significant effects in the treatment of disorders of the central nervous system, such as spinal cord trauma, but not other diseases, such as stroke.
“The NASCIS II study showed that very high-dose methylprednisolone, when given early enough, protected patients with spinal cord injury or at least improved their outcome,” Dr. Levin said. “In NASCIS III, it was shown that a neuroprotective drug called tirilazed mesylate protected neurons as well as high-dose methylprednisolone.”
Therefore, it is hoped that a neuroprotective agent that will protect retinal ganglion cells will be useful in a disease such as anterior ischemic optic neuropathy, he said.
As far as neuroprotective agents or studies on the horizon, Dr. Levin said it is difficult to predict the future, as clinical studies take 3 to 5 years to progress. “Other agents are being considered as possible neuroprotective therapies … there is much interest in agents that increase the viability of neurons after injury,” he said.
On the horizon
Several drugs hold promise for having neuroprotective effects. At the meeting of the Association for Research in Vision and Ophthalmology last year, Neville N. Osborne, PhD, DSc, of the Nuffield Laboratory of Ophthalmology, University of Oxford, presented results of a study that established the ability of betaxolol to interact with neurotoxin site 2 of the sodium channel. Inhibiting this channel may have a role in its neuroprotective action in models of excitotoxicity and ischemia. By reducing the influx of sodium and calcium into retinal ganglion cells, betaxolol may also have a neuroprotective effect in glaucoma, Dr. Osborne said.
He said that his research showed that all beta-blockers interact with L-type calcium and sodium channels to reduce their influx, and that betaxolol is the most potent at reducing their influx. “The calcium and sodium channel blocking characteristics of betaxolol provide a means of protecting the entire ganglion cell,” Dr. Osborne said.
Dr. Dreyer said that there has been significant interest in the use of calcium channel blockers to block ganglion cell death in glaucoma. Also, nitric oxide has been implicated in neuronal death in many systems. “Consequently, agents that block nitric oxide are excellent candidates to block neuronal loss,” he said. “None have been approved as yet for that particular purpose, and, unfortunately, it is not a simple story.”
Dr. Levin believes that a new and exciting approach to neuroprotection involves the concept of retinal ganglion cell death, or apoptosis. “There is a huge amount of basic research over the past several years to understand the mechanisms by which the cells ‘commit suicide.’ Therefore, there has been a lot of interest in using agents that might affect the apoptosis cascade in diseases where apoptosis is one of the cardinal features.”
For Your Information:
- Evan B. Dreyer, MD, PhD, can be reached at the Scheie Eye Institute, 51 N. 39th St., Philadelphia, PA 19104; (215) 662-8078; fax: (215) 662-0133.
- Leonard A. Levin, MD, PhD, can be reached at the Department of Ophthalmology and Visual Science at the University of Wisconsin Medical School, K6/456 CSC, 600 Highland Ave., Madison, WI 53792-4673; (608) 265-6546. Dr. Levin is a paid consultant for several companies studying neuroprotection.
- Robert N. Weinreb, MD, is professor of ophthalmology and director, UCSD Glaucoma Center. He can be reached at the Glaucoma Center/0946, University of California-San Diego, 9500 Gilman Dr., La Jolla, CA 92093; (858) 534-8824; fax: (858) 534-1625.
- Neville N. Osborne, PhD, DSc, can be reached at the Nuffield Laboratory of Ophthalmology, University of Oxford, Walton St., Oxford OX2 6AW, United Kingdom; (44) 1865-248996; fax: (44) 1865-794508.